N-(Ergoline-8β-carbonyl)ureas have shown potent dopamine agonist properties and have been useful as anti-Parkinson drugs and as prolactin inhibitors (U.S. Pat. No. 5,382,669 and Eur. J. Med. Chem. 1989, v 24, 421). One of the most potent prolactin inhibitors of this class is N-3-[(dimethylamino)propyl]-N-[(ethylamino)carbonyl]-6-(2-propenyl)-ergoline-8β-carboxamide (Cabergoline, 1).

Cabergoline displays a significant inhibitory effect with respect to prolactin and has therapeutic properties that make it possible to treat patients who have pathological conditions associated with an abnormal prolactin level. Thus, Cabergoline is useful in human and/or veterinary medicine. The uses of Cabergoline are, for example, described in WO99/48484, WO99/36095, U.S. Pat. No. 5,705,510, WO95/05176, and EP040325. Cabergoline is particularly useful in the treatment of Parkinson's disease (PD), Restless Legs Syndrome (RLS), Progressive Supranuclear Palsy (PSP) and Multysystemic atrophy (MSA).
Cabergoline was first prepared by reaction of 6-(2-propenyl)-ergoline-8β-carboxylic acid 2 with 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide 3 in tetrahydrofuran (THF) or N,N-dimethylformamide (DMF) (U.S. Pat. No. 4,526,892, Eur. J. Med. Chem. 1989, v 24, 421) (Scheme 1):

Both regioisomers 1 and 4 were obtained and the selectivity was poor (1:1 to 2:1). Therefore, the purity of the isolated Cabergoline is low as a consequence of isolation difficulties. Compounding this deficiency is the fact that there is no process to recover and recycle the undesired isomer 4.
The second method for Cabergoline preparation (Eur. J. Med. Chem. 1989, v 24, 421 and GB 2,103,603) was based on the direct reaction of N-[3-(dimethylamino)propyl]-6-(2-propenyl)-ergoline-8β-carboxamide with ethyl isocyanate (Scheme 2):

However, this approach uses hazardous ethyl isocyanate at elevated temperature. It requires a large excess of ethyl isocyanate (up to 40 eq.) for reasonable conversion since this reaction is controlled by the equilibrium between 5 and 1. Also, it must be conduced at 100° C. in toluene, which is 40° C. above the boiling point of ethyl isocyanate. The use of the large quantities of toxic isocyanate under drastic reaction conditions presents a major limitation for the large-scale preparation of Cabergoline by this route. In addition to the safety-related issues, conversion to Cabergoline is incomplete and competitive acylation of the indole nitrogen to give compounds 6 and 7 represents a serious side reaction that reduces yield and complicates product purification.

The method disclosed in U.S. Pat. No. 5,382,669 and Syn. Lett. 1995, 605 is based on the copper salt catalyzed reaction of ethyl isocyanate with carboxamide using phosphorous ligands. Under the optimum conditions, the reaction can be carried out at room temperature with only 3 eq. of ethyl isocyanate. However, despite these moderate reaction conditions, conversion to the product is incomplete (ca. 80%) and the product distribution and degree of conversion is similar to the uncatalyzed thermal reaction. The use of heavy metal ions in the final step of the preparation is also a drawback of this process given the tight specifications surrounding pharmaceutical actives.
WO 02/085902 disclosed a preparation of Cabergoline by silylation of carboxamide followed by treatment with ethyl isocyanate and desilylation (Scheme 3). However, this approach introduced two extra chemical steps and still employed the toxic reagent, ethyl isocyanate.

Another method for the preparation of Cabergoline (J. Org. Chem. 2002, v 67, 7147-7150) is described in Scheme 4. The indole nitrogen of the carboxamide is protected using a tert-butoxycarbonyl (Boc) group, and the product reacts sequentially with phenyl chloroformate and ethylamine. After removal of Boc group, Cabergoline is obtained. However, from a commercial standpoint introduction of multiple chemical steps would significantly increase process cost and the formation of impurity 9 is also a problem.

All the Cabergoline processes described above do not allow for the preparation of the advanced intermediate, 6-(2-propenyl)-ergoline-8β-carboxylic acid 2 or its derivatives. J. Labelled Compound and Radiopharm. 1991, v 29, 519-533, discloses the preparation of 2 from 8β-methoxycarbonylergoline, which in turn may be prepared from Lysergic acid (U.S. Pat. No. 4,166,182). However, Lysergic acid is a controlled substance and therefore has very limited availability which is obviously a severe limitation if commercial production of Cabergoline and its intermediates from this starting material was considered.
It is therefore an object of this invention to provide an efficient and cost-effective synthetic method for the preparation of Cabergoline, and intermediates thereof, from commercially non-restricted starting materials.
Further and other objects of the invention will be realized by those skilled in the art from the following summary of the invention and detailed description of embodiments of the invention.